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Media type:
E-Article
Title:
Modulation of T-Cell Activation by Malignant Melanoma Initiating Cells
Contributor:
Schatton, Tobias;
Schütte, Ute;
Frank, Natasha Y.;
Zhan, Qian;
Hoerning, André;
Robles, Susanne C.;
Zhou, Jun;
Hodi, F. Stephen;
Spagnoli, Giulio C.;
Murphy, George F.;
Frank, Markus H.
Published:
American Association for Cancer Research (AACR), 2010
Published in:
Cancer Research, 70 (2010) 2, Seite 697-708
Language:
English
DOI:
10.1158/0008-5472.can-09-1592
ISSN:
1538-7445;
0008-5472
Origination:
Footnote:
Description:
AbstractHighly immunogenic cancers such as malignant melanoma are capable of inexorable tumor growth despite the presence of antitumor immunity. Thus, only a restricted minority of tumorigenic malignant cells may possess the phenotypic and functional characteristics needed to modulate tumor-directed immune activation. Here we provide evidence supporting this hypothesis. Tumorigenic ABCB5+ malignant melanoma initiating cells (MMICs) possessed the capacity to preferentially inhibit IL-2–dependent T-cell activation and to support, in a B7.2-dependent manner, induction of CD4+CD25+FoxP3+ regulatory T cells (Tregs). Compared with melanoma bulk cell populations, ABCB5+ MMICs displayed lower levels of MHC class I, aberrant positivity for MHC class II, and lower expression levels of the melanoma-associated antigens MART-1, ML-IAP, NY-ESO-1, and MAGE-A. Additionally, these tumorigenic ABCB5+ subpopulations preferentially expressed the costimulatory molecules B7.2 and PD-1, both in established melanoma xenografts and in clinical tumor specimens. In immune activation assays, MMICs inhibited mitogen-dependent human peripheral blood mononuclear cell (PBMC) proliferation and IL-2 production more efficiently than ABCB5− melanoma cell populations. Moreover, coculture with ABCB5+ MMICs increased the abundance of Tregs, in a B7.2 signaling-dependent manner, along with IL-10 production by mitogen-activated PBMCs. Consistent with these findings, MMICs also preferentially inhibited IL-2 production and induced IL-10 secretion by cocultured patient-derived, syngeneic PBMCs. Our findings identify novel T-cell modulatory functions of ABCB5+ melanoma subpopulations and suggest specific roles for these MMICs in the evasion of antitumor immunity and in cancer immunotherapeutic resistance. Cancer Res; 70(2); 697–708